Recent advances in the use of genetically engineered vaccines to prevent outbreaks of infectious disease has prompted a re-evaluation of vaccination strategies against a number of pathogens, including those responsible for sexually-transmitted diseases such as HIV, HSV1, HSV2 and HPV. We have been developing a unique approach to immunization that involves the design and engineering of antigen fusion proteins that are compatible with liposome-based delivery systems. The liposomal vaccine delivery vehicle that we have designed is innovative in that it involves the production and isolation of a fusion protein consisting of a recombinant antigen fused to a hydrophobic protein domain, which is then mixed with lipids and processed to form small unilamellar liposomes with diameters of approximately 100nm. Collectively, the size of the liposome, phospholipid bilayer structure and membrane associated antigenic fusion protein mimic the appearance of an enveloped virus particle to the immune system. In addition, the association of the hydrophobic domain of the antigen fusion protein with the lipid bilayer results in the reproducible incorporation and display of multiple copies of the target antigen/epitope with the liposomes. The small size of the liposomes ensures that they will readily distribute throughout the lymphatic system when administered subcutaneously resulting in high concentrations of antigen in immune tissues which should promote a specific, strong immune response. One of the primary objectives of this project is to develop a safe HSV2 vaccine that is capable of providing a level of protection in male and female human populations which is better than other recombinant vaccines. The nature of Herpes genitalis suggests that an effective vaccine for this disease will likely have to stimulate a potent T-cell mediated immune response in order to control both primary and recurrent infection. We have recently demonstrated that HSV2-gD epitope vaccines based on our approach are capable of protecting both female and male mice from lethal mucosal HSV2 challenge (intravaginal and intrarectal, respectively) and further, actively stimulates effective T-cell immune responses in both sexes. The studies proposed in this application are thus focused on selecting a lead HSV2 vaccine candidate for clinical development that will ultimately produce a vaccine against HSV2, which has so far proven difficult. [unreadable] [unreadable] [unreadable]